Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants. Some of the more important retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and hepatic carcinomas in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. An inhibitor of a retroviral protease should provide a therapeutic agent for diseases caused by the retrovirus.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. 53 899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani, Chem. Eng. News, Nov. 23, 1987 pp. 41-49) involve administration of compounds such as 2',3'-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, 3'-azido-3'-deoxythymidine, and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Inhibitors of HIV protease are disclosed by Moore, Biochem. Biophys. Res. Commun., 159 420 (1989); Billich, J. Biol. Chem., 263 1790S (1988); Richards, FEBS Lett., 247 113 (1989); Miller, Science 246 1149 (1989); Meek, Nature 343 90 (1990); McQuade, Science 247 454 (1990); Sigal, et al., European Patent Application No. EP0337714, published Oct. 18, 1989; Kempf, et al., PCT Patent Application No. WO89/10752, published Nov. 16, 1989; Molling, et al., European Patent Application No. EP354522, published Feb. 14, 1990; Sigal, et al., European Patent Application No. EP357332, published Mar. 7, 1990; Handa, et al., European Patent Application No. EP346847, published Dec. 20, 1989; Desolms, et al, European Patent Application No. EP356223, published Feb. 28, 1990; Schirlin, et al., European Patent Application No. EP362002, published Apr. 4, 1990; Dreyer, et al., PCT Patent Application No. W090/00399, published Jan. 25, 1990; and Hanko, et al., European Patent Application No. EP361341, published Apr. 4, 1990.
U.S. Pat. No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Patent No. 4,644,055 discloses halomethylketone derivatives of peptides as inhibitors of viral proteases.
None of the references mentioned above disclose or suggest the invention claimed herein.
The compounds (A-X-B) shown in Table 1 are disclosed in the following list of references. None of these references disclose or suggest the use of these compounds as inhibitors of retroviral protease or as antiviral agents.
1. S. Apparao, et al., Synthesis, 896 (1987). PA0 2. A. Padwa, et al., J. Chem. Soc. Perkin Trans. I, 2639 (1988). PA0 3. M. McKervey, et al., Tet. Let., 23 2509 (1982). PA0 4. M. Fujiwara, et al., Chem. Abstr. 91:149446. PA0 5. C. Piantadosi, et al., J. Med. Chem., 222 (1976). PA0 6. M. Midland, et al., J. Org. Chem., 39 732 (1974). PA0 7. R. Dybas, et al., U.S. Patent No. 4172094, published Oct. 23, 1979. PA0 8. A. Hosomi, et al., Chem. Pharm. Bull., 36 3736 (1988). PA0 9. K. Taniguchi, et al., Chem. Abstr. 108:29541. PA0 10. R. Freidlina, et al., Chem. Abstr. 57:16464. PA0 11. T. Morikawa, Chem. Abstr. 54:19588. PA0 12. M. Sorokin, et al., Chem. Abstr. 108:111518. PA0 13. G. Ostroumova, Chem. Abstr. 72:56187. PA0 14. T. Kamijo, et al., Chem. Pharm. Bull., 31 4189 (1983). PA0 15. T. Takeda, et al., Bull. Chem. Soc. Jpn., 57 1863 (1984). PA0 16. S. Kukalenko, et al., Chem. Abstr. 78:71621. PA0 17. K. Ito, et al., Chem. Pharm. Bull., 27 1691 (1979). PA0 18. H. Kleiner, Chem. Abstr. 73:45598. PA0 19. G. Rawson, et al., Tetrahedron, 26 5653 (1970). PA0 20. M. Il'ina, et al., Chem. Abstr. 70:37885. PA0 21. E. Regel, et al., U.S. Patent No. 4,618619, issued Oct. 21, 1986. PA0 22. V. Plakhov, et al., Chem Abstr. 73:30312. PA0 23. K. Dathe, et al., Chem. Abstr. 84:73203. PA0 24. W. Wegener, et al., Chem. Abstr. 77:101763. PA0 25. E. Mukhametzyanova, et al., Chem. Abstr. 71:39096. PA0 26. K. Petrov, et al., Chem. Abstr. 74:141977. PA0 27. H. Gilman, et al., Chem. Abstr. 89:172760. PA0 28. T. Hosokawa, et al., Bull. Chem. Soc. Jpn., 58 194 (1985). PA0 29. G. Olah, et al., Synthesis, 221 (1980). PA0 R.sub.201 and R.sub.202 are independently selected from PA0 R.sub.203 is loweralkyl; PA0 R.sub.204 is loweralkyl; PA0 R.sub.205 and R.sub.206 are independently selected from PA0 R is hydrogen or halogen; PA0 R' is hydrogen, halogen, loweralkyl, -NH.sub.2, -NH(loweralkyl) or -OR.sub.206 wherein R.sub.206 is defined as above; PA0 R" is -NH.sub.2, -NH(loweralkyl) or OR.sub.206 wherein R.sub.206 is independently defined as above; PA0 R'" is halogen; and PA0 q is 2 or 3. PA0 A is PA0 B is: PA0 (i) loweralkyl, PA0 (ii) aryl, PA0 (iii) thioalkoxyalkyl PA0 (iv) (aryl)alkyl, PA0 (v) cycloalkyl, PA0 (vi) cycloalkylalkyl, PA0 (vii) hydroxyalkyl, PA0 (viii) alkoxyalkyl, PA0 (ix) aryloxyalkyl, PA0 (x) haloalkyl, PA0 (xi) carboxyalkyl, PA0 (xii) alkoxycarbonylalkyl, PA0 (xiii) aminoalkyl, PA0 (xiv) (N-protected)aminoalkyl, PA0 (xv) alkylaminoalkyl, PA0 (xvi) ((N-protected)(alkyl)amino)alkyl, PA0 (xvii) dialkylaminoalkyl, PA0 (xviii) guanidinoalkyl, PA0 (xix) loweralkenyl, PA0 (xx) heterocyclic, PA0 (xxi) (heterocyclic)alkyl, PA0 (xxii) hydrogen, PA0 (xxiii) arylthioalkyl, PA0 (xxiv) arylsulfonylalkyl, PA0 (xxv) (heterocyclic)thioalkyl, PA0 (xxvi) (heterocyclic)sulfonylalkyl, PA0 (xxvii) (heterocyclic)oxyalkyl, PA0 (xxviii) arylalkoxyalkyl, PA0 (xxix) arylthioalkoxyalkyl, PA0 (xxx) arylalkylsulfonylalkyl, PA0 (xxxi) (heterocyclic)alkoxyalkyl, PA0 (xxxii) (heterocyclic)thioalkoxyalkyl, PA0 (xxxiii) (heterocyclic)alkylsulfonylalkyl, PA0 (xxxiv) cycloalkyloxyalkyl, PA0 (xxxv) cycloalkylthioalkyl, PA0 (xxxvi) cyloalkylsulfonylalkyl, PA0 (xxxvii) cycloalkylalkoxyalkyl, PA0 (xxxviii cycloalkylthioalkoxyalkyl, PA0 (xxxiv) cycloalkylalkylsulfonylalkyl, PA0 (xl) aminocarbonyl, PA0 (xli) alkylaminocarbonyl, PA0 (xlii) dialkylaminocarbonyl, PA0 (xliii) aroylalkyl, PA0 (xliv) (heterocyclic)carbonylalkyl, PA0 (xlv) polyhydroxyalkyl, PA0 (xlvi) aminocarbonylalkyl, PA0 (xlvii) alkylaminocarbonylalkyl and PA0 (xlviii) dialkylaminocarbonyalkyl; PA0 with the proviso that R.sub.3 and R.sub.207 are not both hydrogen. PA0 R.sub.500 is PA0 Z is PA0 R.sub.4 is PA0 R.sub.5 and R.sub.6 are independently selected from PA0 R.sub.7 is PA0 R.sub.8 is PA0 ff is 1 or 2; PA0 n is 0-3; and PA0 m is 1-4. PA0 (i) hydrogen, PA0 (ii) loweralkyl, PA0 (iii) cycloalkyl, PA0 (iv) aryl, PA0 (v) arylalkyl, PA0 (vi) (aryl)alkoxyalkyl PA0 (vii) (aryl)alkoxyalkyl, PA0 (viii) aminoalkyl, PA0 (ix) N-protected-aminoalkyl, PA0 (x) alkylaminoalkyl, PA0 (xi) (N-protected)(alkyl)aminoalkyl, PA0 (xii) dialkylaminoalkyl, PA0 (xiii) carboxyalkoxyalkyl, PA0 (xiv) (alkoxycarbonyl)alkoxyalkyl, PA0 (xv) carboxyalkyl, PA0 (xvi) alkoxycarbonylalkyl, PA0 (xvii) (amino)carboxyalkyl, PA0 (xviii) ((N-protected)amino)carboxyalkyl, PA0 (xix) (alkylamino)carboxyalkyl, PA0 (xx) ((N-protected)alkylamino)carboxyalkyl, PA0 (xxi) (dialkylamino)carboxyalkyl, PA0 (xxii) (amino)alkoxycarbonylalkyl, PA0 (xxiii) ((N-protected)amino)alkoxycarbonylalkyl, PA0 (xxiv) (alkylamino)alkoxycarbonylalkyl, PA0 (xxv) ((N-protected)alkylamino)alkoxycarbonylalkyl, PA0 (xxvi) (dialkylamino)alkoxycarbonylalkyl, PA0 (xxvii) aminocycloalkyl, PA0 (xxviii) alkoxyalkyl, PA0 (xxix) (polyalkoxy)alkyl, PA0 (xxx) heterocyclic, PA0 (xxxi) (heterocyclic)alkyl, PA0 (xxxii) N-protecting group, PA0 (xxxiii) (hydroxyamino)alkyl, PA0 (xxxiv) (alkoxyamino)alkyl, PA0 (xxxv) cycloalkylalkyl, PA0 (xxxvi) loweralkenyl, PA0 (xxxvii) hydroxyalkyl, PA0 (xxxviii) dihydroxyalkyl, PA0 (xxxix) (alkoxy)(alkyl)aminoalkyl, PA0 (xl) alkylaminocycloalkyl, PA0 (xli) dialkylaminocycloalkyl and PA0 (xlii) polyhydroxyalkyl; and PA0 -NR.sub.15 R.sub.16 wherein R.sub.15 and R.sub.16 are PA0 independently selected from hydrogen, PA0 loweralkyl, hydroxyalkyl, alkoxyalkyl, PA0 dihydroxyalkyl, haloalkyl, aminoalkyl, PA0 alkylaminoalkyl, aryl, arylalkyl, PA0 (heterocyclic)alkyl, heterocyclic, PA0 dialkylaminoalkyl, (N-protected)aminoalkyl, PA0 (N-protected)alkylaminoalkyl, cyanoalkyl, PA0 hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, PA0 (amino)carboxyalkyl, PA0 ((N-protected)amino)carboxyalkyl, PA0 (alkylamino)carboxyalkyl, PA0 ((N-protected)alkylamino)carboxyalkyl, PA0 (dialkylamino)carboxyalkyl, PA0 (amino)alkoxycarbonylalkyl, PA0 ((N-protected)amino)alkoxycarbonylalkyl, PA0 (alkylamino)alkoxycarbonylalkyl, PA0 ((N-protected)alkylamino)alkoxycarbonylalkyl and PA0 (dialkylamino)alkoxycarbonylalkyl.
(In the table "Ph" represents phenyl).
TABLE 1 ______________________________________ A X B ______________________________________ PhOCH.sub.2 C(O) PhSCH.sub.2 PhS(O).sub.2 CH.sub.2 C(O) PhCH.sub.2 CH.sub.2 PhCH.sub.2 CH.sub.2 C(O) PhSCH.sub.2 PhS(O).sub.2 CH.sub.2 C(O) PhS(O).sub.2 CH.sub.2 PhOCH.sub.2 C(O) PhOCH.sub.2 PhS(O)CH.sub.2 C(O) PhCH.sub.2 CH.sub.2 PhSCH.sub.2 C(O) PhSCH.sub.2 PhCH.sub.2 CH.sub.2 C(O) PhCH.sub.2 CH.sub.2 PhCH.sub.2 CH.sub.2 CH(OH) PhSCH.sub.2 PhOCH.sub.2 CH(OH) PhOCH.sub.2 PhS(O).sub.2 CH.sub.2 CH(OH) PhS(O).sub.2 CH.sub.2 PhCH.sub.2 CH.sub.2 CH(NH.sub.2) PhCH.sub.2 CH.sub.2 PhNHCH.sub.2 CH(OH) PhOCH.sub.2 PhNHCH.sub.2 CH(OH) PhNHCH.sub.2 PhCH.sub.2 CH.sub.2 CH(OH) PhCH.sub.2 CH.sub.2 PhCH.sub.2 CH.sub.2 CH(OH) PhSCH.sub.2 PhOCH.sub.2 CH(OH) PhSCH.sub.2 PhNHCH.sub.2 CH(OH) PhSCH.sub.2 PhSCH.sub.2 CH(OH) PhSCH.sub.2 PhCH.sub.2 CH.sub.2 N(OH) PhCH.sub.2 CH.sub.2 PhSCH.sub.2 N(OH) PhSCH.sub.2 PhCH.sub.2 CH.sub.2 P(OH)(H) PhCH.sub.2 CH.sub.2 PhS(O).sub.2 CH.sub.2 N(OH) PhS(O).sub.2 CH.sub.2 PhNHCH.sub.2 P(O)(OH) PhNHCH.sub.2 PhOCH.sub.2 ##STR1## PhOCH.sub.2 PhCH.sub.2 CH.sub.2 S(O).sub.2 PhCH.sub.2 CH.sub.2 PhS(O).sub.2 CH.sub.2 S(O).sub.2 PhS(O).sub.2 CH.sub.2 PhSCH.sub.2 P(O)(OH) PhSCH.sub.2 PhOCH.sub.2 P(O)(OH) PhOCH.sub.2 PhCH.sub.2 CH.sub.2 P(O)(OH) PhCH.sub.2 CH.sub.2 PhNHCH.sub.2 P(O)(OH) PhNHCH.sub.2 PhCH.sub.2 CH.sub.2 S(O) PhCH.sub.2 CH.sub.2 PhCH.sub.2 CH.sub.2 C(NOH) PhCH.sub.2 CH.sub.2 ______________________________________